Early experiences in life greatly influence and shape the human brain. Vulnerability to neuropsychiatric diseases later in life may be due to interruption of prefrontal cortex (PFC) maturation by negative environmental influences during sensitive periods of development. Some studies suggest that women are more vulnerable than men to the second hit of early life adversity.

Kelsea Gildawie, Lilly Ryll, Jessica C. Hexter, Shayna Peterzell, Alissa Valentine, led by Professor Heather Brenhouse from Northeastern University, investigated the long-term, sex-specific, cumulative effects of multiple developmental stressors that are associated with psychiatric disorders, and they published their findings in the journal Developmental Cognitive Neuroscience.

They sought to determine how newborn separation from caregivers, followed by a second hit of social isolation from peers, might have female-specific compounding effects on PFC perineuronal nets—meshes of sugars and proteins that help neurons adapt and grow—and if that contributes to anxiety-like behaviour susceptibility.  Kelsea Gildawie performed behaviour testing on rats after separation from their mother and later social isolation. Later they used immunohistochemistry, microscopy and image quantification to show differences to expose differences among individuals.

One of the essential findings of this critical study is that in females, but not males, social isolation from peers can reverse some detrimental effects that neonatal adversity has on the way the animal responds to potential threats in the environment; however, when looking at other types of behaviors that indicate anxiety, neonatal adversity could protect females from detrimental effects of juvenile social isolation.  When the researchers looked at the cellular level in the brain, they found that both hits of adversity had a compounding effect on the perineuronal nets that help neurons communicate with each other.

Professor Brenhouse explains, “these findings are important because they suggest that the developing female brain takes information from very early life and processes it in a way that impacts the way she perceives and responds to later threats—threats that include isolation from peers while growing up, as well as later-life threats in adulthood.  The male brain appears to process these same types of traumas differently, and it is possible that could cause different types of vulnerability and resilience between the two sexes.”  Their data show that the double hit of adversity yields a higher long-term impact on perineuronal net structural integrity and parvalbumin cell count in females. 

“In the current study, we observed a sex-specific effect of adversity on hyperactivity and risk-assessment behavior; however, contrary to findings in the brain, the pattern of results was not additive in nature,” said Ms. Gildawie. This could suggest that anxiety-like behavioural changes are not wholly caused by adversity-induced parvalbumin and perineuronal disruption and that other processes may be at stake. Later she added: “Future work will investigate other prefrontal cortex-mediated behaviors that may be regulated by alterations in neurostructural maturation, such as social behavior and working memory.”

This novel study has tremendous potential to inform scientists and clinicians interested in the impacts of early life adversity because it points to significant differences in the way males and females alter their development when exposed to these kinds of stressors. Thus, we can better understand neuropsychiatric sequelae and possibly improve the preventive treatments.

Journal Reference and Main Image Credit:

Gildawie KR, Ryll LM, Hexter JC, Peterzell S, Valentine AA, Brenhouse HC. A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior. Dev Cogn Neurosci. 2021 Apr;48:100924. DOI: 10.1016/j.dcn.2021.100924. Epub 2021 Jan 27.

About the Authors

Dr. Heather Brenhouse, Ph.D.

Associate Professor

Dr. Heather Brenhouse is an Associate Professor in the Department of Psychology at Northeastern University. She received her B.S. in Psychobiology from Binghamton University, her M.S. in Behavioral and Systems Neuroscience from Rutgers University, and her PhD. in Experimental Psychology from Northeastern University. She did her post-doctoral work at Harvard Medical School, McLean Hospital, was an Instructor at Harvard Medical School, and then in 2012 joined the Behavioral Neuroscience and Psychology faculty at Northeastern.

Kelsea Gildawie, M.S.

Ph.D. Candidate

Kelsea Gildawie is a Ph.D. Candidate at Northeastern University in the Developmental Neuropsychobiology Laboratory, led by Dr. Heather Brenhouse. She received her B.S. in Neuroscience and Behavior from Simmons University, where she investigated the role of nutrition on age-related cognitive decline in mice. Her current research involves the sex-dependent neuroimmune and neurostructural impacts of early life adversity throughout development and corresponding behavioral disruption.